EP0993829B1 - Transdermal preparation containing serotonin receptor antagonist - Google Patents

Transdermal preparation containing serotonin receptor antagonist Download PDF

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Publication number
EP0993829B1
EP0993829B1 EP97946064A EP97946064A EP0993829B1 EP 0993829 B1 EP0993829 B1 EP 0993829B1 EP 97946064 A EP97946064 A EP 97946064A EP 97946064 A EP97946064 A EP 97946064A EP 0993829 B1 EP0993829 B1 EP 0993829B1
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EP
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Prior art keywords
medicine
sensitive adhesive
layer
pressure
weight percent
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Expired - Lifetime
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EP97946064A
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German (de)
English (en)
French (fr)
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EP0993829A4 (en
EP0993829A1 (en
Inventor
Munehiko Hisamitsu Pharm. Co. Inc. HIRANO
Masayoshi Hisamitsu Pharm. Co. Inc. MAKI
Tatsuaki Hisamitsu Pharm. Co. Inc. SUZUKI
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Hisamitsu Pharmaceutical Co Inc
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Hisamitsu Pharmaceutical Co Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to a percutaneous therapeutic apparatus for delivery of a serotonin receptor antagonist.
  • the apparatus may enable control of ooze of liquid medicine from a drug storage layer during preservation of the apparatus by laminating a pressure-sensitive adhesive for controlling ooze of medicine to a drug releasing surface.
  • the apparatus may enable administration of the predetermined amount of the serotonin-receptor antagonist precisely and certainly to a patient.
  • a percutaneous therapeutic apparatus such as Estraderm, Nitorderm and so forth have been conventionally developed and used clinically.
  • adhesion of the apparatus to skin decreases due to an interaction with medicine during preservation.
  • Such decline of adhesion of a patch medicine during administration causes a decline of area for absorbing medicine and there is a case where blood concentration of drug sufficient for therapeutics can not be obtained, which may be possibly a deadly problem to the patch medicine.
  • Several percutaneous therapeutic apparatuses have been proposed in which a medicine releasing surface and a pressure-sensitive adhesive layer having to do with adhesion to skin are separated.
  • Unexamined Patent Publication (Kokai) No. 61-265150 discloses an example in which a medicine storage layer is separated from an adhesive existing on the outer periphery of the medicine storage layer by a circumferential seal.
  • Unexamined Patent Publication (Kokai) No. -1283 and Unexamined Patent Publication (Kokai) No. 62-212320 are common to Unexamined Patent Publication (Kokai) No. 61-265150 on the point that an interaction of the pressure-sensitive adhesive layer on the periphery of the medicine releasing surface with the medicine storage layer are disconnected.
  • EP A 965342 relevant under Article 54(3) EPC, provides a percutaneous preparation comprising an adhesive layer formed on at least one side of a substrate, the layer containing an acrylic copolymer, 6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole or an acid additions of thereof and 2-mercaptobenzimidazole.
  • JP 8034731 provides a percutaneous formulation comprising granisetron or a pharmaceutically acceptable salt, together with a percutaneous absorption agent.
  • JP 6199659 provides an apparatus for percutaneous administration comprising a porous material having a medicine release material layer for releasing medicine from a medicine storage tank to skin.
  • the problem to be solved by this invention is to get rid of lowering adhesion resulting from an interaction of an apparatus with medicine during preservation of the apparatus and increase of skin irritation accompanying the enlargement of bulk caused by placing a pressure-sensitive adhesive layer on the periphery.
  • this invention relates to an apparatus for supplying to skin surface an effective amount of serotonin-receptor antagonist for therapeutics from a liquid medicine storage layer through a medicine releasing layer and, more particularly, relates to a percutaneous therapeutic apparatus the medicine-releasing surface of which is sealed to make a loss in medicine substantially zero when using the apparatus and which is able to apply to a patient the predetermined amount of the serotonin-receptor antagonist precisely and certainly.
  • the percutaneous therapeutic apparatus of this invention having a medicine-release layer comprising a pressure-sensitive layer which is able to control release of the drug, good adhesion can be obtained and increase of skin irritation resulting from enlarged bulk can be prevented and, simultaneously, ooze of the medicine can be prevented during preservation and an effective amount of the medicine for therapeutics can be released precisely and certainly from the present apparatus after sticking the present apparatus on to the skin of a patient.
  • this invention provides a percutaneous therapeutic apparatus which enables
  • This invention relates to a percutaneous therapeutic apparatus for delivery of a serotonin receptor antagonist medicine selected from granisetron hydrochloride, azasetron hydrochloride, ondansetron hydrochloride, ramosetron hydrochloride, ( + )-8,9-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl)methyl] pyrido [1,2-a] indole-6 (7H)-on hydrochloride, (R)-5-(2,3-dihydro-1H-indol-1-ylcarbonyl)-4, 5, 6, 7-tetrahydro-1H-benzimidazole-hydrochloride and Endo-N-(3,9-dimethyl-3, 9 diazabicyclo [3,3,1] non-7-yl)-1H-indazole-3-carboxyamide dibasic acid salt, which apparatus is characterised by having at least three layers comprising:
  • the percutaneous therapeutic apparatus of this invention can be provided with a release liner layer which is able to be released when using outside the aforementioned medicine-releasing layer.
  • the medicine-releasing layer of this invention which controls the release of medicine may comprise a medicine-permeable film (hereinafter, sometimes referred to as porous layer) and the pressure-sensitive adhesive layer.
  • the serotonin-receptor antagonist which can be administered stably over a long period of time.
  • a pressure-sensitive adhesive layer which is able to control release of the medicine and which comprises a pressure-sensitive adhesive containing a rubber elastomer, tackifier resin and softening agent and optionally an acrylic type pressure-sensitive adhesive.
  • a percutaneous therapeutic apparatus having a layer structure shown in Fig. 1 can be given as one embodiment of the percutaneous therapeutic apparatus of this invention.
  • liquid medicine containing a therapeutically effective amount of drug components is encapsulated in a medicine storage layer 2 between the backing layer 1 and a porous material 3 of a medicine-permeable film.
  • a pressure-sensitive adhesive layer 4 is laminated to outer layer of porous material 3 and coated with a release liner 5 for sealing medicine, which release liner 5 is released when using this invention.
  • Fig. 2 is a view of a state as seen from the side of skin when removing a release liner 5 of the percutaneous therapeutic apparatus of this invention.
  • the press layer 6 is pressed somewhat deeply along the outer periphery of the effective releasing surface at the portion where the medicine-permeable film and the backing material are sealed in order to seal the medicine storage layer 2. Since the medicine is not stored between the release liner 5 and the pressure-sensitive adhesive layer 4 by virtue of the presence of the pressure-sensitive adhesive layer 4, there is no chance for loss in medicine when releasing the release liner 5.
  • the medicine can be released from the medicine-releasing layer 3.
  • the drug contained in the medicine storage layer of the apparatus of this invention is serotonin-receptor antagonist, and may be preferable antagonist for 5-T 3 and / or 5-HT 4 receptor, one of sub-types of serotonin-receptor which is used as antiemetic in order to control vomiting occurring often when administering chemotherapeutics for cancer chemothrapy.
  • the serotonin-receptor antagonist is chosen from granisetron hydrochloride, azasetron hydmchloride, ondansetron hydrochloride, ramosetron hydrochloride (the above names are general names), (+)-8,9-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl)methyl]pyrido[1,2-a] indole-6(7H)-on hydrochloride, (R)-5-(2,3-dihydro-1H-indol-1-ylcarbonyl)-4, 5, 6,7-tetrahydro-1H-benzimidazole-hydrochloride and Endo-N-(3,9-dimethyl-3, 9-diazabicyclo[3,3,1]non-7-yl)-1H-indazole-3-carboxyamide dibasic acid salt (the above names are chemical names).
  • serotonin-receptor antagonists may be in a state of liberation or pharmaceutically acceptable organic or inorganic salt.
  • the amount of the serotonin-receptor antagonist is sufficient amount effective for therapeutics, and may be preferable, for example, 0.1-10 weight percent. And, the combined-use of more than two kinds of these medicines may be acceptable, if necessary.
  • the aforementioned drugs used in this invention are preferably formed in a state of liquid or semisolid (ointment) by adding the other components thereto and stored in the medicine storage layer.
  • the compounding ratio of water may be preferably 20-70 weight percent and the compounding ratio of lower alcohol may be preferably 10-40 weight percent.
  • the compounding ratio of absorption enhancer such as aliphatic alcohol and so forth may be preferably 0.1-10 weight percent.
  • the compounding ratio of wetting agent such as glycerine, polyethylene glycol and so forth may be preferably 20-40 weight percent.
  • the compounding ratio of irritation-reducing agent such as glycerol monooleate or glycerol monolaurate or mixture thereof may be preferably 1-10 weight percent.
  • the absorption enhancer used in this invention may be preferable aliphatic acid, aliphatic alcohol or ester of aliphatic acid having 7-20 carbon atoms, and, above all, lauryl alcohol and myristyl alcohol may be more preferable since they exhibit high absorption enhancer property and relatively poor irritation to skin.
  • a wetting agent may be preferable sorbitol, polyethylene glycol, diglycerin, propylene glycol, butylene glycol, dipropylene glycol, sodium pyrrolidone carboxylate, ethyl carbitol, D-xylitol, glycerin, hyaluronic acid, and, above all, glycerin or polyethylene glycol may be particularly preferable.
  • the water component is preferably a buffer solution.
  • the irritation-reducing agent an ester of aliphatic acid or ester of sorbitol aliphatic acid or mixture thereof is prefered.
  • the preferred lower alcohols may be particulary ethanol or isopropanol.
  • gelling agent may be added to these components if necessary.
  • the proper gelling agent to be used may be exemplified by carboxyvinyl polymer, sodium polyacrylic acid, polyvinyl pyrrolidone, hydroxydipropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose.
  • UV-absorbing agent such as anti-oxidant, antiseptic and so forth may be added, if necessary.
  • the ultraviolet-absorbing agent may be exemplified by publicly-known para-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumalic acid derivatives, amino acid derivatives, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, furan derivatives, pyrone derivatives, camphor derivatives, nucleic acid derivatives, allantoin derivatives, nicotinic acid derivatives, shikonin or vitamin-6 derivatives, and benzophenone derivatives such as 2-hydroxy-4-methoxybenzophenone derivatives and so forth may be more preferably used.
  • antioxidant may be exemplified by ascorbic acid, ester of stearic acid, sodium ascorbate, tocopherol (d-form, 1-form, d, 1-form of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol and so forth) and ester derivatives thereof, nordihydroguaceretic acid, dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroxynon, ester of Gallic acid (ester of ethyl, propyl, isoamyl and so forth) 1-oxo-3-methyl-4-isopropylbenzene.
  • the film for the backing layer should be excellent in so-called barrier properties in order to prevent ooze and vaporization of medicine and should have such properties as to be easily bonded to porous material of the medicine-releasing layer. And, it is also preferable that the film for the backing layer has modest softness when the apparatus of this invention is stuck to skin.
  • the material of the backing layer is not particularly limited even if it has the aforementioned requirements and may be exemplified by aluminum, ethylene-vinylacetate copolymer or saponified products thereof, cellulose acetate, cellulose, Nylon, polyester, polyethylene, polyvinylidene chloride, polycarbonate, polyvinylalcohole, polypropylene.
  • these materials may be used in a form of a film, or in a form of a laminated film prepared by laminating these materials in a form of paper or cloth to a film, or may be used after being deposited with aluminum or ceramic thereon.
  • the materials constituting the medicine-releasing film is porous and may be exemplified by ethylene-vinylacetate copolymer, cellulose, cellulose acetate, polyester, polyethylene, polypropylene and so forth.
  • the porous materials have preferably 10-500 sec/100 cc of Gurley permeability.
  • the pressure-sensitive adhesive layer which is able to control release of medicine has sufficient adhesive force to attach the apparatus of this invention to skin.
  • the pressure-sensitive adhesive layer of this invention makes use of pressure-sensitive adhesive comprising rubber elastomer, tackifier resin and softening agent, and may also comprise an acrylic type pressure-sensitive adhesive in addition to these three components.
  • the pressure-sensitive adhesive layer of this invention is prepared by applying the aforementioned pressure-sensitive adhesive to whole area of the medicine- releasing layer.
  • the rubber elastomer may be preferably exemplified by polyisobutylene (for example, polyisobutylene available from Exxon Chemicals as trade name " Vistanex” or from BASF as trade name " Oppano 1”), (A-B) n-Type elastic polymer (for example, styrene-butadiene- styrene block copolymer available from Shell Chemicals as trade name "Cariflex TR-1101”), styrene-isoprene-styrene block copolymer (available from Shell Chemicals as trade name " Cariflex TR-1107", “ Cariflex TR-1111”), styrene-isoprene-styrene block copolymer (available from Japan Synthetic Rubber co., Ltd.
  • polyisobutylene for example, polyisobutylene available from Exxon Chemicals as trade name " Vistanex” or from BASF as trade name " Oppano 1
  • A-B n-
  • the compounding ratio of the rubber elastomer in the pressure-sensitive adhesive may be 5-50 weight percent, preferably 10-40 weight percent, more preferably 10-30 weight percent.
  • the tackifier resin a component of the pressure-sensitive adhesive, may be exemplified by alicyclicsaturated hydrocarbon resin (for example, "Arcon P-100” (trade name), rosin ester (for example, “KE-311", “KE-100” (trade name), " Super Ester S-100 " (trade name), hydrogenated petroleum resin (for example, "Foral 105" (trade name), terpene-series hydrogenated petroleum resin (for example, "Cryalone P-105" (trade name).
  • the compounding ratio of the tackifier resin in the pressure-sensitive adhesive maybe 5-50 weight percent, preferably 5-40 weight percent, more preferably 10-35 weight percent.
  • the softening agent a component of the pressure-sensitive adhesive
  • the softening agent may be exemplified by liquid paraffin, polybutene, castor oil, cottonseed oil, palm oil, coconut oil, process oil.
  • the compounding ratio of the softening agent in the pressure-sensitive adhesive may be 10-70 weight percent, preferably 15-60 weight percent, more preferably 20-50 weight percent.
  • An acrylic adhesive which is able to be used simultaneously with the rubber elastomer as a component for the pressure-sensitive adhesive may be preferably, particularly, homopolymer of (meth) acrylic acid alkyl ester having alkyl group having 4-18 carbon atoms, or copolymer thereof, or copolymer of the above-mentioned (meth) acrylic acid alkyl ester and the other functional monomer.
  • (meth) acrylic acid alkyl ester may be exemplified by butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, iso-octyl acrylate, decyl acrylate, iso-decyl acrylate, lauryl acrylate, stearyl acrylate, methyl methacrylate, ethyl methacryate, butyl methacryate, iso-butyl methacrylate, 2-ethylhexyl methacryate, iso-octyl methacryate, decyl methacryate, iso-decyl methacryate, lauryl methacrylate, stearyl methacryate.
  • the above-mentioned functional monomer may be exemplified by monomer having a hydroxyl group, monomer having a carboxyl group, monomer having an amide group, a monomer having an amino group, a monomer having a pyrrolidone ring.
  • the monomer having a hydroxyl group may be exemplified by hydroxyalkyl (meth) acrylate such as 2-hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate and so forth.
  • the monomer having a carboxyl group maybe exemplified by ⁇ , ⁇ -unsaturated carboxylic acid such as acrylic acid, methacrylic acid and so forth, ester of maleic acid and monoalkyl such as butyl maleate and so forth, maleic acid, fumaric acid, crotonic acid.
  • Maleicanhydride is also a component for copolymer similarly to maleic acid.
  • the monomer having an amide group may be exemplified by alkyl (meth) acrylic amide such as acrylic amide, dimethylacrylic amide, diethylacrylic amide and so forth, N-alkoxymethyl (meth) acrylic amide such as N-butoxymetylacrylic amide, N-ethoxymetylacrylic amide and so forth, diacetonacrylic amide.
  • the monomer having an amino group may be exemplified by dimethylaminoethylacrylate and so forth.
  • the monomer having a pyrrolidone ring may be exemplified by N-vinyl-2-pyrrolidone.
  • the compounding ratio of the acrylic type pressure-sensitive adhesive may be 0-80 weight percent (means 0 weight percent in the case of single use of rubber elastomer), preferably 5-60 weight percent, more preferably 10-30 weight percent.
  • the film thickness of the pressure-sensitive adhesive layer may be preferably 30 ⁇ 300 ⁇ m, and a problem occurs in adhesion when it is thinner than 30 ⁇ m, and, in contrast, there occurs a case where the control of release is difficult when it is thicker than 300 ⁇ m,
  • the percutaneous therapeutic apparatus having safety to skin and release control containing serotonin (5-HT 3 and/or 5-HT 4 )-receptor antagonist of this invention is prepared by combination of these elastomer, tackifier resin, softening agent and/or acrylic type pressure-sensitive adhesive.
  • additives may be added, if necessary, to the pressure-sensitive adhesive layer of this invention for adjustment of adhesive, safety and stability, more concretely, water-absorbing polymer such as "SUMIKAGEL SP-520" (trade name), “AQUA KEEP 4 SH” (trade name), “ARASOAP 800 F” (trade name), “SUNWET 1M-1000 HPS” (trade name), inorganic additives such as zinc oxide, calcium carbonate, titanium dioxide, silica, solubilizer such as polyethylene glycol, crotamiton may be added properly in a suitable amount.
  • water-absorbing polymer such as "SUMIKAGEL SP-520" (trade name), "AQUA KEEP 4 SH” (trade name), “ARASOAP 800 F” (trade name), “SUNWET 1M-1000 HPS” (trade name)
  • inorganic additives such as zinc oxide, calcium carbonate, titanium dioxide, silica, solubilizer such as polyethylene glycol, crotamiton may be added properly in a suitable amount.
  • the film constituting the release liner layer has to prevent ooze or vaporization of medicine from the medicine-releasing layer during the preservation of the apparatus of this invention, and the release liner layer should be removed when using the apparatus.
  • the material of the release liner film may be used aluminum, cellulose, polyester, polyethylene, polypropylene and so forth, which may be used in a form of a laminated film thereof, if necessary. And, it is not objectionable that releasability or barrier property is adjusted by treating the surface of the material of the release liner film with silicon or fluorocarbon or by adding well-known additives to the material of the liner.
  • the release liner may be provide with a lug for releasing in order to make handling when releasing easy.
  • the medicine-releasing layer and the release liner covering thereon should be bonded each other during the preservation of the apparatus, and such release liner has to be released to remove when using the apparatus. Therefore, the adhesive force between the medicine-releasing layer and the release liner covering thereon must be lower that that of between the backing layer and the medicine-releasing layer.
  • the form of the apparatus is not particularly restricted, but may be exemplified by circle, ellipse, polygon.
  • the area of the apparatus may be preferably 1 cm 2 -200 cm 2 . In the case where the area is narrower than 1 cm 2 , it is difficult to release the release liner to stick on skin, and in the case where the area is larger than 200 cm 2 , the feel of wearing is bad.
  • the thickness of the apparatus may be preferably 0.1-15 mm in overall thickness of the apparatus including the release liner. In the case where the thickness is thinner than 0.1 mm, since the amount of medicine to be administered per the medicine-releasing area is unavoidably diminished and the persistency of releasing the medicine is shortened, it is not preferable. In the case where the thickness is thicker than 15 mm, since there is high possibility that the apparatus is removed by unexpected action of a patient, it is not preferable.
  • the percutaneous therapeutic apparatus of this invention thus prepared has a structure in which the medicine is encapsulated between the backing layer and the medicine-releasing layer, it can accept any medicine having a wide range of viscosity from liquid-state medicine of low viscosity to that of high viscosity and it has the merit for preferable design of the safety, stability and effectiveness because it has a wide range of selection of the composition of medicine compared with a tape-medicine and so forth.
  • the method of preparing the percutaneous absorption medicine of this invention is not particularly restricted, but any conventional method can be adopted.
  • every component of the pressure-sensitive adhesive layer is dissolved in an organic solvent such as hexane, toluene, ethyl acetate, and thereafter spread on the release liner to remove the organic solvent.
  • the pressure-sensitive adhesive layer opposite to the release liner is coated with a porous material to prepare the medicine-releasing layer which is then cut to desired form, and 0.5g of medicine prepared independently are added dropwise to the side of the porous material which is then heat-sealed with the backing layer and thereafter cut along the outer periphery of the heat-seal, thereby, the percutaneous therapeutic apparatus of this invention can be obtained.
  • the medicine which is able to be stored in the percutaneous absorption pharmaceutical composition can be prepared by treating properly lower alcohol, wetting agent, water, irritation-reducing agent, absorption enhancer and medicine to prepare by means of emulsification testing machine (NIKKO CHEMICAL ET-3A).
  • styrene-isoprene-styrene block copolymer 10.5 acrylic type pressure-sensitive adhesive 10.0 (2-ethylhexyl acrylate / vinyl acetate copolymer) liquid paraffin 49.3 tackifier (alicyclicsaturated hydrocarbon resin) 20.0 polyisobutylene 10.0 dibutyl hydroxytoluene 0.2
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • styrene-isoprene-styrene block copolymer 30.0 acrylic type pressure-sensitive adhesive 5.0 (2-ethylhexyl acrylate/ethyl acrylate-vinyl acetate copolymer) liquid paraffin 30.5 tackifier (alicyclic saturated hydrocarbon resin) 25.0 polyisobutylene 5.0 polyethylene glycol 200 4.0 dibutyl hydroxytoluene 0.5
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • styrene-isoprene-styrene block copolymer 15.0 acrylic type pressure-sensitive adhesive 11.5 (2-ethylhexyl acrylate/vinyl pyrrolidone copolymer) liquid paraffin 14.5 tackifier (rosin ester) 35.0 polyisobutylene 15.0 crotamiton 5.0 sunwet 1M-1000 MPS 3.0 dibutyl hydroxytoluene 1.0
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • composition of the pressure-sensitive adhesive Composition of the pressure-sensitive adhesive
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • composition of the pressure-sensitive adhesive Composition of the pressure-sensitive adhesive
  • styrene-isoprene-styrene block copolymer 25.0 liquid paraffin 42.0 tackifier (alicyclic saturated hydrocarbon resin) 20.0 polyisobutylene 8.0 polyethylene glycol 200 4.0 diibutyl hydroxytoluene 1.0
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • styrene-isoprene-styrene block copolymer 12.0 acrylic type pressure-sensitive adhesive 5.5 (2-ethylhexyl acrylate / methyl acrylate copolymer) liquid paraffin 23.0 tackifier (alicyclic saturated hydrocarbon resin) 50.0 polyisobutylene 8.0 diibutyl hydroxytoluene 1.5
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • styrene-isoprene-styrene block copolymer 10.0 acrylic type pressure-sensitive adhesive 30.0 (2-ethylhexyl acrylate/vinyl pyrrolidone copolymer) liquid paraffin 29.0 tackifier (alicyclic saturated hydrocarbon resin) 20.0 polyisobutylene 10.0 diibutyl hydroxytoluene 1.0
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • ethanol 24.0 buffer water solution 40.0 polyethylene glycol 400 25.0 lauryl alcohol 0.5 glycerine monooleate 3.0 sorbitan monolaurate 1.0 hydroxypropylimethyl cellulose 4000 2.0 ondansetron hydrochloride 4.0
  • composition of the pressure-sensitive adhesive Composition of the pressure-sensitive adhesive
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • composition of the pressure-sensitive adhesive Composition of the pressure-sensitive adhesive
  • styrene-isoprene-styrene block copolymer 14.0 acrylic type pressure-sensitive adhesive 5.0 (2-ethylhexyl acrylate / vinyl pyrrolidone copolymer) liquid paraffin 70.0 tackifier (alicyclic saturated hydrocarbon resin) 10.0 dibutyl hydroxytoluene 1.0
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • styrene-isoprene-styrene block copolymer 5.0 acrylic type pressure-sensitive adhesive 80.0 (2-ethylhexyl acrylate / methyl acrylate copolymer) liquid paraffin 10.0 tackifier (alicyclic saturated hydrocarbon resin) 5.0
  • the pressure-sensitive adhesive was prepared from the above-described formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • the pressure-sensitive adhesive was prepared from the above-desc ribed formulation in accordance with the aforementioned method and laminated with porous material, thereafter was cut to desired shape to form a medicine-releasing layer.
  • acrylic type pressure-sensitive adhesive (TS-620: Nippon Carbide Co., Ltd.) Composition of medicine ethanol 24.0 buffer water solution 40.0 glycerine 25.0 lauryl alcohol 0.5 glycerine monoleate 3.0 sorbitan monolaurate 1.0 sodium carboxymethylcellulose 3.5 ondansetron hydrochloride 3.0
  • the above-described acrylic type pressure-sensitive adhesive (TS-620) was spread over a removably treated film so that the thickness after drying is approximately 50 ⁇ m, and organic solvent is removed.
  • a circular fine quality paper 5 cm 2 in surface area is laminated to the adhesive, and porous material is laminated thereon.
  • 0.5 g of the medicine independently prepared are added dropswise to the porous material on which the fine quality paper is laminated and then is heatsealed with a backing layer to form a heatsealed laminate.
  • the laminate thus obtained is cut in the shape of circle 20 cm 2 in surface area so as to position the heatseal at center to prepare a specimen.
  • acrylic type pressure-sensitive adhesive 97.0 (TS-620: trade name for Nippon Carbide Co., Ltd.) solid content ondansetron hydrochloride 3.0
  • All components are dissolved in an organic solvent such as hexane, toluene, ethyl acetate and so forth, then were spread over a substrate, and thereafter coated with a liner after removing the solvent to form a laminate. A specimen in desired shape is cut out of the laminate thus prepared.
  • all components are dissolved in an organic solvent such as hexane, toluene, ethyl acetate and so forth, then were spread over a removably treated film, and thereafter were pressed to a proper substrate to transfer thereon to obtain a specimen.
  • styrene-isoprene-styrene block copolymer 25.0 polyisobutylene 5.0 liquid paraffin 42.0 tackifier (alicyclic saturated hydrocarbon resin) 25.0 ondansetron hydrochloride 3.0
  • a specimen was prepared in a manner similar to that of Comparative Example 2.
  • Estraderm TTS (available from Ciba Specialty Chemicals Inc. formerly Ciba Geigy Ltd.)
  • NitrodermTTS available from Ciba Specialty Chemicals Inc. formerly Ciba Geigy Ltd.
  • Adhesive test and skin irritation test were carried out in a manner describe below to each specimen of Examples and the specimens of Comparative Examples 1 and 4 as well as 5.
  • the specimens were patched to brachia of 20 investigational persons (health, male) to evaluate after 72 hours.
  • the results obtained were shown in Tables 1 and 2.
  • Comparative Example 1 1/4-release were observed in most of investigational persons, in contrast, no release was observed in most of investigational persons in Examples.
  • skin irritation obvious erythemata (red spots) were observed in most of investigational persons, in contrast, extremely light erythemata (red spots) were observed in Examples.
  • Table -1 Example 1
  • Example 2 Example 3 Com. Ex.
  • Example 3 The results obtained were shown in Table-3.
  • the change in weight and oozing of medicine were ⁇ in comparative Example 1, but, in contrast, they were ⁇ in Examples.
  • Table-3 Example 1
  • Example 2 Example 3 Ref.
  • Example 1 Change in weight ⁇ ⁇ ⁇ ⁇ oozing of medicine ⁇ ⁇ ⁇ ⁇
  • the percutaneous therapeutic apparatus containing serotonin-receptor antagonist of this invention can get rid of, during preservation of the apparatus, lowering of adhesion resulted from an interaction with medicine and increase of skin irritation accompanying with enlargement of bulk caused by placing a pressure-sensitive layer on the periphery of the apparatus, and, when using the apparatus, can supply an effective amount of drug from a liquid medicine storage layer through a medicine-releasing layer to skin surface and to control release of medicine by virtue of the pressure-sensitive layer covering the whole surface of the medicine-releasing layer.
  • the percutaneous therapeutic apparatus containing serotonin-receptor antagonist and the percutaneous absorption pharmaceutical preparation of this invention is able to administer drugs stably over a long period of time.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Botany (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
EP97946064A 1996-12-11 1997-11-28 Transdermal preparation containing serotonin receptor antagonist Expired - Lifetime EP0993829B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP34646096 1996-12-11
JP8346460A JPH10167956A (ja) 1996-12-11 1996-12-11 セロトニン受容体拮抗薬含有経皮投与製剤
PCT/JP1997/004358 WO1998025592A1 (fr) 1996-12-11 1997-11-28 Preparation transdermique contenant un antagoniste des recepteurs de la serotonine

Publications (3)

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EP0993829A1 EP0993829A1 (en) 2000-04-19
EP0993829A4 EP0993829A4 (en) 2001-10-31
EP0993829B1 true EP0993829B1 (en) 2011-01-12

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US (1) US6495159B2 (ko)
EP (1) EP0993829B1 (ko)
JP (1) JPH10167956A (ko)
KR (1) KR100529515B1 (ko)
CN (1) CN1135971C (ko)
CA (1) CA2274111A1 (ko)
DE (1) DE69740099D1 (ko)
WO (1) WO1998025592A1 (ko)

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DE10015783C2 (de) * 2000-03-30 2003-12-04 Lohmann Therapie Syst Lts Transdermales therapeutisches System zur Abgabe von Lerisetron und seine Verwendung
JP4792193B2 (ja) * 2002-08-28 2011-10-12 久光製薬株式会社 貼付剤
JP4213432B2 (ja) * 2002-08-28 2009-01-21 久光製薬株式会社 貼付剤
US7785622B2 (en) * 2002-09-13 2010-08-31 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch for fentanyl administration
GB0302662D0 (en) * 2003-02-05 2003-03-12 Strakan Ltd Transdermal granisetron
ES2449042T3 (es) * 2003-07-31 2014-03-18 Hisamitsu Pharmaceutical Co., Inc. Parche adhesivo
JP2008511663A (ja) * 2004-09-01 2008-04-17 ネクスメツド・ホールデイングス・インコーポレイテツド 経皮制吐送達系、そのための方法および組成物
JP4804007B2 (ja) 2005-01-13 2011-10-26 日東電工株式会社 粘着製品
CN101180018B (zh) * 2005-05-18 2014-02-26 亚贝丽制药公司 用于治疗恶心的经皮的方法和贴片
US20060263421A1 (en) * 2005-05-18 2006-11-23 Abeille Pharmaceuticals Inc Transdermal Method and Patch for Nausea
CN101984764A (zh) * 2008-04-02 2011-03-09 爱多克产品股份有限公司 固定太阳能模件到基底上的体系与方法
WO2010008632A1 (en) * 2008-04-02 2010-01-21 Adco Products, Inc. Adhesive composition and method for attaching a component to a substrate
WO2009139411A1 (ja) 2008-05-15 2009-11-19 久光製薬株式会社 パロノセトロンを含有する経皮吸収製剤
CN102413821A (zh) 2009-05-01 2012-04-11 久光制药株式会社 经皮吸收型制剂
WO2012029325A1 (ja) * 2010-09-03 2012-03-08 株式会社ケイ・エム トランスダーム 経皮吸収製剤および皮膚貼付用粘着シート
CN102000044A (zh) * 2010-11-25 2011-04-06 沈阳药科大学 阿扎司琼经皮贴剂及其制备方法

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JPH02149514A (ja) * 1988-04-06 1990-06-08 Nitto Denko Corp 医薬部材
JPH0834731B2 (ja) 1990-09-10 1996-03-29 株式会社学研クレジット モザイク模様形成機
JP3030076B2 (ja) * 1990-11-01 2000-04-10 三菱電機株式会社 電流制御回路
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JPH06199659A (ja) * 1992-10-28 1994-07-19 Hisamitsu Pharmaceut Co Inc 経皮治療用装置
JPH0748258A (ja) * 1993-06-03 1995-02-21 Kanebo Ltd 経皮投与用製剤
JPH0834731A (ja) * 1994-07-26 1996-02-06 T T S Gijutsu Kenkyusho:Kk グラニセトロン含有経皮吸収型製剤
JP3238409B2 (ja) * 1994-09-16 2001-12-17 久光製薬株式会社 外用貼付剤
JPH09315976A (ja) 1996-05-29 1997-12-09 Nitto Denko Corp 経皮投与用製剤

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CA2274111A1 (en) 1998-06-18
KR20000057419A (ko) 2000-09-15
JPH10167956A (ja) 1998-06-23
DE69740099D1 (de) 2011-02-24
CN1135971C (zh) 2004-01-28
US20020102290A1 (en) 2002-08-01
US6495159B2 (en) 2002-12-17
CN1240350A (zh) 2000-01-05
EP0993829A4 (en) 2001-10-31
WO1998025592A1 (fr) 1998-06-18
EP0993829A1 (en) 2000-04-19
KR100529515B1 (ko) 2005-11-22

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